Alzheimer""s disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Pathological hallmarks include neurofibrillary tangles (paired helical filaments) and amyloid deposits within the parenchyma and cerebral vasculature.
Recent studies indicate that a major component of the pathology of Alzheimer""s disease is chronic inflammation. See, J. Schnabel, Science, 260:1719-1720 (1993). Administration of nonsteroidal anti-inflammatory drugs appears to slow the advance of Alzheimer""s disease. Understanding this inflammatory component of Alzheimer""s disease may lead to advances in methods of treating patients suffering from this disease.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids.
The scientific literature suggests NSAIDs may be beneficial in the treatment of Alzheimer""s Disease. Moreover, COX-2 inhibitors are currently being tested for treatment of Alzheimer""s.
PLA2 inhibitors have been proposed as treatment for Alzheimer""s disease (see, U.S. Pat. No. 5,478,857), but tykpically these have been cytosolic phospholipase A2 inhibitors.
Because of the debilitating effects of Alzheimer""s disease there continues to exist a need for effective treatments. This invention provides methods for the treatment of Alzheimer""s disease in mammals.
This invention is a method of treating a mammal, including a human, susceptible to having Alzheimer""s disease, to prevent or delay the onset of Alzheimer""s disease; said method comprising administering to said mammal a prophylactically effective amount of 1H-indole-3-glyoxylamide sPLA2 inhibitor or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.
This invention is also a method of treating a mammal, including a human, already afflicted with Alzheimer""s disease to prevent or diminish the rate of further deterioration; said method comprising administering to said mammal a therapeutically effective amount of 1H-indole-3-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.